PROJECT SUMMARY/ABSTRACT Anal cancer is the second most common non-AIDS defining cancer and a leading cause of morbidity among HIV-infected (HIV+) persons in the United States (US). The incidence of anal cancer increases with age. With nearly 50% HIV+ persons are now 50-years or older, preventative health care in the form of screening is a major public health priority to decrease their risk of developing anal cancer. Because anal cancer is biologically similar to cervical cancer, current guidelines (inferred from cervical cancer literature) recommend screening HIV+ men and women using anal cytology for detection of high-grade squamous intraepithelial lesions (the anal cancer precursor); however, optimal screening regimen (age to start and stop screening as well as optimal screening frequency) for the prevention of anal cancer still remains unknown. Due to the lack of clear understanding of harms versus benefits of screening, only 11% of HIV+ persons had an anal cytology in the preceding year, leading to 50% of diagnoses occurring at stage III or worse when the 5-year survival rate is less than 40%. The goal of the proposed research is to identify appropriate candidates for screening and determine age- specific screening algorithms to reduce anal cancer morbidity and mortality among HIV+ men and women. We will integrate evidence from two large clinical trials and several large databases into mathematical modeling, a complementary approach to randomized clinical trials. In Aim 1, we will measure the impact of age and HIV disease status (i.e., HIV viral suppression, CD4 count) on the incidence of anal HSIL, HSIL recurrence, and progression to anal cancer. In Aim 2, we will develop a clinically-valid mathematical model of anal cancer natural history in HIV+ men and women and use it to determine optimal age-specific anal cancer screening algorithm. Finally, in Aim 3, we propose to determine the minimum necessary efficacy (by age) of anal HSIL treatment for HIV+ men and women to provide clinically significant benefits for screening and finally determine areas of future research to improve the value of anal cancer screening. The proposed research is innovative because it applies advanced modeling approach with multiple datasets to address a problem that has not been solved by empirical methods. The research team is ideally suited, with an established track record in HIV and HPV epidemiology, cancer outcomes research, and clinical care, having substantial experience in developing mathematical models to inform clinical decision making. The end results of the proposed study will be age-specific anal cancer screening recommendations for HIV+ men and women that will inform anal cancer prevention policies and practice and ultimately reduce morbidity and mortality.